Circulating vitamin D levels are inversely associated with prostate cancer risk and supplementation with vitamin D for prostate cancer prevention has been proposed. We recently developed a mouse model of adult prostate progenitor/stem cells (PrP/SC). The adult tissue specific stem cell may be an important target for chemoprevention. We have interrogated the effects of the active metabolite of vitamin D, 1a,25-dihydroxyvitamin D3 [1,25(OH)2D3], on the PrP/SC. 1,25(OH)2D3 blocks proliferation, induces cell cycle arrest, and increases expression of cyclin-dependent kinase inhibitors p21 and p27. Our data suggest that 1,25(OH)2D3 promotes differentiation of the PrP/SC. Consistent with prodifferentiation we observe increased androgen receptor (AR) expression in 1,25(OH)2D3-treated PrP/SC. To identify novel targets of vitamin D receptor transcriptional activity and to assess global gene expression changes we probed gene expression arrays with RNA from 1,25(OH)2D3-treated PrP/SC. We identified a signaling pathway that is both necessary and sufficient for 1,25(OH)2D3 antiproliferative actions on the PrP/SC and is required for induction of AR. Preliminary data also demonstrate a moderate cell cycle block and a more profound induction of senescence, which is dependent on this pathway. This project will interrogate the role of this pathway in vitamin D signaling in the prostate stem cell in more detail. We will evaluate the mechanism of regulation by vitamin D and how this pathway intersects with AR signaling, we will determine the signaling pathway leading to senescence in response to vitamin D both in vitro and in vivo, and we will test the ability of vitamin D to block prostate tumor progression in a genetic model of prostate cancer that exhibits progression through prostatic intraepithelial neoplasia in a p27-dependent manner. Overall these studies will impact our understanding of the effects of vitamin D signaling on prostate stem cell growth arrest, differentiation and senescence and the functional roles of vitamin D in the prevention of prostate tumor progression. PUBLIC HEALTH RELEVANCE: Prostate cancer is a significant health problem in the US which is a candidate disease for chemoprevention strategies. This project will dissect the underlying mechanisms of vitamin D-induced changes on the prostate stem cell, a viable target for chemoprevention strategies. This project will further our efforts to develop rationale chemoprevention strategies for prostate cancer.